Preconditioning (PC) is the well-described phenomenon whereby brief episodes of myocardial ischemia render cardiomyocytes resistant to a later, sustained ischemic insult. However, evidence from our group has shown that PC has an ancillary, favorable effect on the maintenance of vessel patency in models of recurrent thrombosis mimicking clinical instances of acute ischemic syndromes. We hypothesized, in our previous application, that: (1) the enhanced patency seen with PC ischemia is due to a PC-induced attenuation in one or more molecular indices of platelet activation-aggregation; and (2) adenosine liberated during the PC stimulus, and resultant stimulation of adenosine A2 receptors on the platelets' surface, serves as the trigger for the improved patency. The first concept was supported by novel evidence of a significant, PC-induced down-regulation of platelet P-selectin expression, platelet-fibrinogen binding, and formation of neutrophilplatelet aggregates (NPAs). However, this favorable attenuation in molecular indices of platelet reactivity was not explained solely by platelet-A2 receptor stimulation. Accordingly, our aim in this competitive renewal is to expand upon the platelet-A2 receptor paradigm and investigate the concept that the improved vessel patency initiated by PC ischemia is a consequence of a complex interplay among multiple triggers (i.e., adenosine and bradykinin) acting at multiple sites (receptors on neutrophils as well as platelets). Two hypotheses are proposed: (I) Neutrophils (i.e., formation of NPAs and activation of neutrophil L-selectin) contribute to the pathophysiology of recurrent thrombosis. Moreover, release of adenosine during PC ischemia contributes to the improved maintenance of vessel patency by an A2-mediated down-regulation of neutrophil L-selectin activation. (II) Release of bradykinin during PC ischemia, and its rapid breakdown and production of stable bradykinin metabolites, contribute to the PC-induced augmentation of arterial patency via stimulation of platelet PAR4 receptors. These hypotheses will be tested by an integrated analysis of physiologic and molecular-cellular endpoints (i.e., arterial patency in concert with state-of-the-art flow cytometric quantitation of platelet and neutrophil activation) in multiple in vivo models of recurrent thrombosis (from dogs, to rats, to genetically modified mice). The resulting mechanistic insights may, ultimately, be exploited in the future design of novel therapies for the clinical treatment of recurrent thrombosis.